Total synthesis of dihydroclerodin from (R)-(-)-carvone

Article abstract of DOI:10.1021/jo991151r

The first total synthesis of the natural enantiomer of the insect- antifeedant dihydroclerodin (1) and lupulin C (40) has been achieved starting from (R)-(-)-carvone (2). In the applied strategy, the hexahydrofuro[2,3- b]furan moiety was introduced in an early stage of the synthesis: The correct configuration at C-9, C-11, C-13, and C-16 was established by application of a remarkably diastereoselective Mukaiyama reaction. The desired configuration at C-10 was obtained by catalytic reduction of the intermediate enone 21. After annulation of the second ring, the structural features at C-4, C-5, and C-6 were introduced. The successful finishing of the synthesis included a Chugaev elimination to give the exocyclic double bond at C-4 that is present in lupulin C. Oxidation of this double bond with m-CPBA afforded dihydroclerodin.

Full text of DOI:10.1021/jo991151r

9178
J . Org. Chem. 1999, 64, 9178-9188
Tota l Syn th esis of Dih yd r ocler od in fr om (R)-(-)-Ca r von e
Tommi M. Meulemans, Gerrit A. Stork, Fliur Z. Macaev,† Ben J . M. J ansen, and
Aede de Groot*
Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8,
6703 HB Wageningen, The Netherlands
Received J uly 20, 1999
The first total synthesis of the natural enantiomer of the insect-antifeedant dihydroclerodin (1)
and lupulin C (40) has been achieved starting from (R)-(-)-carvone (2). In the applied strategy,
the hexahydrofuro[2,3-b]furan moiety was introduced in an early stage of the synthesis. The correct
configuration at C-9, C-11, C-13, and C-16 was established by application of a remarkably
diastereoselective Mukaiyama reaction. The desired configuration at C-10 was obtained by catalytic
reduction of the intermediate enone 21. After annulation of the second ring, the structural features
at C-4, C-5, and C-6 were introduced. The successful finishing of the synthesis included a Chugaev
elimination to give the exocyclic double bond at C-4 that is present in lupulin C. Oxidation of this
double bond with m-CPBA afforded dihydroclerodin.
Sch em e 17
In tr od u ction
Diterpenoids possessing the clerodane skeleton (Scheme
1) are widely distributed in nature, and new members of
this subclass of diterpenes continue to appear in the
literature.1-3 Of the relatively few clerodanes that were
tested for biological activity, many were found to possess
interesting properties, which vary from antifeedant to
antiviral, antitumor, antibiotic, antipeptic ulcer, and
piscicidal activity.2
Despite the fact that so many clerodanes have been
isolated, only a few were synthesized.4 So far only one
total synthesis is known of a clerodane that is oxidized
in the A and in the B ring as well as on C-18.1 To our
knowledge, nobody yet has succeeded in the total syn-
thesis of a clerodane with a chiral center at the difficult
C-11 position. Much effort was put into tackling this prob-
lem of the stereochemistry at C-11 by Lallemand et al.5
and in our group,6 but it proved to be difficult to develop
strategies in which either a hexahydrofuro[2,3-b]furan
fragment could be attached to a completed decalin part
or in which the decalin part could be finished with an
already attached hexahydrofuro[2,3-b]furan moiety.
* To whom correspondence should be addressed. E-mail:
Aede.deGroot@bio.oc.wau.nl. Fax: (031)317484914. Tel: (031)317482370.
† Institute of Chemistry, Academy str. 3, MD-2028 Kishinev,
Republic of Moldova.
(1) J ones, P. S.; Ley, S. V.; Simpkins, N. S.; Whittle, A. J .
Tetrahedron 1986, 42, 6519-6534.
(2) Merrit, A. T.; Ley, S. V. Nat. Prod. Rep. 1992, 9, 243-287.
(3) Tokoroyama, T. Yuki Gosei Kagaku Kyokaishi 1993, 51, 1164-
1177.
We now wish to report on the total synthesis of the
natural enantiomer of dihydroclerodin and lupulin C,
starting from (R)-(-)-carvone as is depicted in Scheme
1. A new strategy was developed in which the methyl
group at C-8 was introduced first, followed by a remark-
ably diastereoselective Mukaiyama addition of the hexahy-
drofuro[2,3-b]furan moiety, which gave the correct con-
figuration at C-9, C-11, C-13, and C-16.7 Next, the
isopropenyl group was removed and ring A was annu-
lated with the correct stereochemistry at C-10. In the last
stage of the synthesis the characteristic functionalities
at C-5, C-6, and C-4 were introduced.
(4) (a) Reference 1. (b) Xiang, A. X.; Watson, D. A.; Ling, T. T.;
Theodorakis, E. A. J . Org. Chem. 1998, 63, 6774-6775. (c) Kawano,
H.; Itoh, M.; Katoh, T.; Terashima, S. Tetrahedron Lett. 1997, 38,
7769-7772. (d) Kende, A. S.; Roth, B. Tetrahedron Lett. 1982, 23,
1751-1754. (e) Liu, H. J .; Shia, K. S. Tetrahedron 1998, 54, 13449-
13458. (f) Goldsmith, D. J .; Deshpande, R. Synlett 1995, 495-497. (g)
Tokoroyama, T.; Fujimori, K.; Shimizu, T.; Yamagiwa, Y.; Monden,
M.; Iio, H. Tetrahedron 1988, 44, 6607-6622. (h) Piers, E.; Breau, M.
L.; Han, Y.; Plourde, G. L.; Yeh, W.-L. J . Chem. Soc., Perkin Trans. 1
1995, 963-966. (i) Lee, T.-H.; Liao, C.-C. Tetrahedron Lett. 1996, 37,
6869-6872. (j) Takahashi, S.; Kusumi, T.; Kakisawa, H. Chemistry
Lett. 1979, 515-518. (k) Tokoroyama, T.; Kanazawa, R.; Yamamoto,
S.; Kamikawa, T.; Suenaga, H.; Miyabe, M. Bull. Chem. Soc. J pn. 1990,
63, 1720-1728. (l) Bruner, S. D.; Radeke, H.; Tallarico, J . A.; Snapper,
M. L. J . Org. Chem. 1995, 60, 1114-1115. (m) Piers, E.; Wai, J . S. M.
J . Chem. Soc., Chem. Commun. 1988, 1245-1247. (n) Sarma, A. S.;
Chattopadhyay, P. J . Org. Chem. 1982, 47, 1727-1731. (o) Piers, E.;
Roberge, J . Y. Tetrahedron Lett. 1992, 33, 6923-6926. (p) Lio, H.;
Monden, M.; Okada, K.; Tokoroyama, T. J . Chem. Soc., Chem.
Commun. 1987, 358-359. (q) Sharma, A. S.; Gayan, A. K. Tetrahedron
1985, 41, 4581-4592. (r) Tokoroyama, T.; Tsukamoto, M.; Asada, T.;
Lio, H. Tetrahedron Lett. 1987, 28, 6645-6648. (s) Hagiwara, H.;
Inome, K.; Uda, H. J . Chem. Soc., Perkin Trans. 1 1995, 757-764. (t)
Liu, H.-J .; Shia, K.-S.; Han, Y.; Sun, D.; Wang, Y. Can. J . Chem. 1997,
75, 646-655. (u) Watanabe, H.; Onoda, T.; Kitahara, T. Tetrahedron
Lett. 1999, 40, 2545-2548.
Resu lts a n d Discu ssion
The first step of the total synthesis of dihydroclerodin
required a conjugate addition of a methyl group to the
(5) (a) Renard, P. Y.; Lallemand, J . Y. Bull. Soc. Chim. Fr. 1996,
133, 143-149. (b) Ducrot, P.-H.; Hervier, A.-C.; Lallemand, J . Y. Synth.
Commun. 1996, 26, 4447-4457 and references cited herein.
(6) (a) Vader, J .; Koopmans, R.; de Groot, A.; van Veldhuizen, A.;
van de Kerk, S. Tetrahedron 1988, 44, 2663-2674. (b) Vader, J .;
Sengers, H.; de Groot, A. Tetrahedron 1989, 45, 2131-2142.
(7) Throughout the discussion the numbering of the clerodane
skeleton is followed as given by Connolly, J . D.; Hill, R. A. Dictionary
of Terpenoids; Chapman & Hall: New York, 1991; Vol. 1, pp XXXII.
10.1021/jo991151r CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/20/1999

Total Synthesis of Dihydroclerodin
J . Org. Chem., Vol. 64, No. 25, 1999 9179
Sch em e 2a
Sch em e 3
a
Reagents: (a) LiAlH4; (b) TsCl, pyridine; (c) NaCN; (d) NaOH,
H2O; (e) HCl, H2O; (f) seven steps; (g) ICH2CO2SnBu3, AIBN; (h)
DiBALH, BF3-etherate, MeOH.
enone in (R)-(-)-carvone and capturing of the enolate as
its silylenol ether. The isopropenyl group in (R)-(-)-
carvone ensures the correct configuration at C-8, and
investigations with a variety of electrophiles have shown
that the introduction of the second substituent in the ring
takes place from the desired â-side, to give the correct
configuration at C-9.8 For the introduction of the hexahy-
drofuro[2,3-b]furan fragment in ring B, an enantioselec-
tive synthesis of 2-methoxyhexahydrofuro[2,3-b]furan
had to be developed to make sure that the configuration
at C-13 and C-16 would be correct. Finally, this leaves
the stereochemistry at C-11 as an uncertain factor in this
approach, and we intended to investigate several variet-
ies of nonchelated or sterically influenced Mukaiyama
reactions to solve this problem.
For the enantioselective synthesis of 2-methoxyhexahy-
drofuro[2,3-b]furan 8, a resolution of methyl ester 3 was
developed in our laboratory (Scheme 2). Enzymatic
transesterification of 3 with butanol resulted in a mixture
of (R)-methyl- and (S)-butylesters that could be separated
by preparative gas chromatography.9 Starting from ra-
cemic 3, we have shown that this ester can be converted
into 8. This synthesis involved reduction of the ester
followed by tosylation of the resulting alcohol and sub-
sequent substitution of the tosylate in 4 by cyanide to
afford the nitrile 5. Saponification of this nitrile followed
by addition of acid gave the lactone 7 in 91% yield, which
then could be transformed into 8 by reduction and
transacetalization in 62% yield. A seven-step synthesis
of enantiomerically pure 8 has been developed by Furtoss,
starting from cyclobutanone 6.10
mained in solution, and in this way large quantities of
11 could be obtained in a short procedure, which in
practice proved to be much easier than the more laborious
routes using enantiomerically pure 8.
The diastereoselectivity of the Mukaiyama reaction can
be explained by an approach of the silylenol ether to the
less hindered convex side of both enantiomers of the
hexahydrofuro[2,3-b]furan cation, which leads to the
formation of diastereoisomers 11 and 12 (Scheme 3). In
an approach from the concave side of this cation, serious
steric hindrance would be developed between the sub-
stituents on the silylenol ether and C-14 and C-15 of the
hexahydrofuro[2,3-b]furan moiety, and for this reason the
diastereoisomers 11a and 12a are not formed.
The stereochemistry of the crystalline 12 was proven
by X-ray analysis. The oily 11 was reduced to the alcohol
13, which after mesylation and elimination gave the
crystalline diene 14. Structure elucidation by X-ray
crystallography showed that 14 had the desired natural
stereochemistry at C-8, C-9, C-11, C-13, and C-16.12 For
the annulation of ketone 11, a Robinson annulation was
investigated first. This reaction failed in our hands, but
several modifications are under investigation and will be
reported soon. Additions of alkyllithium or alkylmagne-
sium reagents to ketone 11 also failed, most likely due
to steric hindrance of the large hexahydrofuro[2,3-b]furan
moiety in combination with the other substituents. To
reduce the steric congestion, it was decided to remove
the isopropenyl group in this stage of the synthesis. The
isopropenyl has transferred the chirality from C-6 to C-8
and C-9 in the desired sense, and as such, it is not
necessary anymore. Reaction with ozone followed by
However, both syntheses are rather long and give low
overall yields, and it proved unnecessary to use these
methods for the following two reasons. First, we have
found a short route to obtain racemic 8,11 which could be
carried out on a multigram scale starting from enol ether
9 in 56% overall yield. Second, the use of racemic 8 in
the Mukaiyama reaction with silylenol ether 10 proved
to be remarkably diastereoselective. Only two of the
possible eight diastereoisomers were formed, and these
could easily be separated by crystallization of 12 from
diisopropyl ether. The desired diastereoisomer 11 re-
13
treatment of the ozonide with Cu(OAc)2 and FeSO4
yielded the enone 15 (70%), which only could be obtained
after workup using acidic and basic conditions to break
the strong complexation between the metal ions and
compound 15.
(8) Meulemans, T. M.; Stork, G. A.; J ansen, B. J . M.; de Groot, A.
Tetrahedron Lett. 1998, 39, 6565-6568.
(9) Franssen, M. C. R.; J ongejan, H.; Kooijman, H.; Spek, A. L.;
Camacho Mondril, N. L. F. L.; Boavida dos Santos, P. M. A. C.; de
Groot, A. Tetrahedron: Asymmetry 1996, 7, 497-510.
(10) Petit, F.; Furstoss, R. Synthesis 1995, 1517-1520.
(11) Kraus, G. A.; Landgrebe, K. Tetrahedron Lett. 1984, 25, 3939-
3942.
(12) X-ray crystallography was done by Veldman, N.; Menzer, S.;
Spek, A. L. Bijvoet Center for Biomolecular Research, Department of
Crystal and Structural Chemistry, Utrecht University.
(13) Schreiber, S. L. J . Am. Chem. Soc. 1980, 102, 6165-6166.

9180 J . Org. Chem., Vol. 64, No. 25, 1999
Meulemans et al.
Sch em e 4a
Sch em e 5a
a
Reagents: (a) O3, Cu(OAc)2, FeSO4; (b) PhSH, Et3N; (c)
a
Reagents: (a) MeMgI, CuBr.Me2S, HMPA, TMSiCl; (b) Tr-
trichloroisocyanuric acid; (d) LiAlH4; (e) PTSA; (f) pent-4-
enylMgBr, CuBr‚Me2S; (g) O3, Ph3P; (h) PPTS, ∆.
ClO4, 72%; (c) Li-Selectride; (d) MsCl, pyridine; (e) LiBr, Li2CO3.
Sch em e 6a
For the construction of ring A, a four-carbon fragment
had to be introduced at C-10, and for that reason a 1,3-
enone transposition of 15 into 17 was undertaken to set
the stage for a 1,4-addition. It has been shown by Ley et
al.1 that a copper-catalyzed conjugate addition gives the
desired stereochemistry at C-10, when a 1,3-ditihiolan-
2-yl substituent instead of a hexahydrofuro[2,3-b]furan
substituent is present in the molecule at C-9. The 1,3-
ditihiolan-2-yl moiety probably gives a large complex with
the cuprate to block the â-side (axial) of the molecule
allowing a second equivalent of the cuprate to attack from
the desired R-side (equatorial). We had already observed
the complexing capability of the hexahydrofuro[2,3-b]-
furan moiety in the treatment of the ozonide with Cu-
(OAc)2 and FeSO4 and therefore reasoned that this
complexation might also be expected in the 1,4-addition,
causing a similar effect as had been observed for the 1,3-
ditihiolan-2-yl moiety.
To achieve the 1,3-enone transposition, thiophenol was
added to enone 15, followed by chlorination using trichlor-
oisocyanuric acid14 and concomitant dehydrochlorina-
tion,15 to give compound 16 in high yield. Reduction of
the ketone in 16 and hydrolysis of the intermediate then
gave the transposed enone 17 in 74% yield. The 1,4-
addition of 4-pentenylmagnesiumbromide to enone 17
using CuBr‚Me2S as a catalyst gave only one adduct in
88% yield. The configuration at C-10 was determined in
the cyclized decalin 19, which was obtained after ozo-
nolysis of the double bond followed by aldol condensation
(Scheme 5). The stereochemistry of 19 was elucidated by
NMR, where no NOE between H-10 and H-8 could be
detected, whereas a clear NOE was observed between
H-10 and both the methyl groups at C-8 and C-9, which
is indicative for an R-position of this proton. This meant
that the 1,4-addition to enone 17 had occurred from the
â-side, to yield the wrong configuration at C-10. Appar-
ently, the hexahydrofuro[2,3-b]furan moiety does not
show the same effect as the 1,3-ditihiolan-2-yl moiety did
in the synthesis of ajugarin I.1
a
Reagents: (a) 3-(1,3-dioxolan-2-yl)propyllithium 20; (b) PCC;
(c) Pd/C, H2; (d) PPTS, H2O; (e) PPTS, ∆.
On the basis of this experience, it was expected that
also other reagents would approach enones such as 17
from the â-side, because the methyl at C-9 blocks the
approach from the R-side. Therefore, a reaction sequence
was planned in which a four-carbon fragment was
introduced at C-10 followed by addition of hydrogen at
the C-5, C-10 double bond (Scheme 6).
First, the 1,2-addition of a four-carbon fragment to 16
was studied, but this did not yield an enone like 21. The
addition went poorly, and the planned hydrolysis of the
intermediate gave the highly stable diene sulfide as a
product of dehydration in low yield. Hydrolysis of this
diene sulfide could not be achieved. In contrast to the
failure of the 1,2-addition to ketone 11, and the poor yield
of the 1,2-addition to 16, the 1,2-addition of 3-(1,3-
dioxolan-2-yl)propyllithium 20 to the less hindered enone
15 could be accomplished in an acceptable yield of 42%
to give a mixture of alcohols. Due to the basic character
of 20, the deconjugated derivative of enone 15 was
obtained in 25% yield as the major side product.16 This
deconjugated enone could be used again for the 1,2-
addition after reconversion to 15 by treatment with
(14) Mura, A. J .; Bennet, D. A.; Cohen, T. Tetrahedron Lett. 1975,
50, 4433-4436.
(15) (a) de Groot, A.; Peperzak, R. M.; Vader, J . Synth. Commun.
1987, 17, 1607-1616. (b) Bukuzis, P.; Bakuzis, M. L. F. J . Org. Chem.
1981, 46, 235-239.

Total Synthesis of Dihydroclerodin
J . Org. Chem., Vol. 64, No. 25, 1999 9181
Sch em e 7a
Sch em e 8a
a
Reagents: (a) LiAlH4; (b) MeO2CMe2, PPTS; (c) O3, NaBH4;
a
Reagents: (a) vinylMgBr, CuBr‚Me2S, CH2O; (b) TBDMSiCl,
(d) pyridine, MsCl; (e) LiBr, Li2CO3, 100 °C; (f) Ac2O, pyridine,
DMAP.
imidazole; (c) LiAlH4; (d) Ac2O, DMAP; (e) O3, Ph3P; (d) Pyrolidone‚
HBr‚Br2.
MeONa. The mixture of alcohols was submitted to an
oxidative rearrangement17 to yield the transposed enone
21. Catalytic hydrogenation of enone 21 with H2 and Pd/C
afforded one product 22 in 81% yield, and again the
elucidation of the stereochemistry at C-10 was done in
the cyclized decalin 23, which was obtained after depro-
tection of 22 to the aldehyde and subsequent aldol
condensation.18 The correct configuration at C-10 in 23
could be concluded from NMR studies where now a clear
NOE between H-10 and H-8 was observed.
F igu r e 1.
With the top side of the decalin finished, we turned
our attention to the introduction of the two additional
carbons of the clerodane skeleton following the procedure
of Ley.1 The conjugate addition of vinylmagnesium
bromide to 23 and trapping of the enolate with a solution
of monomeric formaldehyde in THF19 introduced the
necessary fragments and established the desired stere-
ochemistry at C-5 in 51% yield. When oxygen was not
fully excluded in this reaction, the hydroperoxy 25 was
obtained as the major product.20 The hydroxymethyl
group was protected as its tert-butyldimethylsilyl ether
26 to prevent hydroxyl-directed reduction of the carbonyl
group. Now reduction of the carbonyl group with LiAlH4
yielded the deprotected diol with the correct configuration
at C-6. The final transformation of the vinyl substituent
at C-4 into an epoxide with the correct stereochemistry
proved to be the last problem, which only could be solved
after major efforts. From the literature1 and from our own
experience,21 it was concluded that the direct oxidation
of an exocyclic double bond at C-4 would probably give
the wrong configuration of the epoxide. The hydroxyl-
directed epoxidation with VO(acac)2 seemed more prom-
ising in this respect, but its chemoselectivity was ques-
tionable, and therefore, the route to construct the epoxide
via a bromohydrine as intermediate was investigated
first.
The two hydroxyl groups that were obtained after the
reduction of 26 were transformed into their acetates to
avoid extra protection-deprotection steps. The double
bond was ozonolyzed and gave aldehyde 27 in 95% yield,
and bromination of this aldehyde gave an 1:4 epimeric
mixture with the axial bromine 28 as the major product
in 63% yield (Scheme 7). The idea was to reduce the
R-bromoaldehyde to an R-bromohydrine, which upon
treatment with base should cyclize to the desired epoxide.
However, the alcohol, obtained after reduction of 28 with
NaBH4, immediately reacted with the acetates to give a
mixture of transposed acetates. An attempt to remove
the acetates by treatment with MeONa before the reduc-
tion gave the ring closed product 29 in 75% yield. An
acetonide as protecting group proved to be no solution,
owing to the instability of the acetonide under the
bromination conditions, and the hemiacetal 30 was
isolated as the main product. Since this approach did not
open an easy route to the desired epoxide, the synthesis
of an exocyclic methylene at C-4 was investigated, to
(16) To prevent this base-catalyzed isomerization the less basic
organocerium reagent was studied in the addition reaction, but this
did not yield the addition product due to the low reactivity of the
organocerium reagent.
(17) Ziegler, F. E.; Wallace, O. B. J . Org. Chem. 1995, 60, 3626-
3636.
(18) PPTS was used as a catalyst for the aldol condensation, because
the more acidic PTSA yielded many side products (see also note 26).
(19) Schlosser, M.; J enny, T.; Guggisberg, Y. Synlett 1990, 704.
(20) For similar fast trapping of enolates by oxygen, see: (a)
Koreeda, M.; You, Z. J . Org. Chem. 1989, 54, 5195-5198. (b) Gallagher,
T. F.; Adams, J . L. J . Org. Chem. 1992, 57, 3347-3353.
(21) Luteijn, J . M.; de Groot, A. Tetrahedron Lett. 1982, 23, 3421-
3424.

9182 J . Org. Chem., Vol. 64, No. 25, 1999
Meulemans et al.
Sch em e 9a
epoxidize this double bond either by VO(acac)2 or by
m-CPBA. A third possibility to obtain the desired epoxide
might be created by ozonolysis of this methylene to a
ketone, which then could be submitted to a Corey
epoxidation.
To obtain the exocyclic methylene group the vinyl
group was ozonolyzed and the ozonide was reduced with
NaBH4 to yield alcohol 32.22 Elimination of the hydroxyl
group in 32 through conversion into a phenylselenide or
via its mesylate was investigated, but formation of the
selenide failed and formation of the mesylate yielded the
deprotected diol mesylate 33, which under elimination
conditions gave 34 in 61% yield.
Finally, 32 was transformed into the xanthate ester
37. Now a Chugaev elimination23 could be tried, and this
elimination indeed gave the exomethylene 38 in 74%
yield. It was difficult to follow this Chugaev reaction by
TLC, because of similar Rf values of 37, 38, and several
side products. Heating at reflux in n-dodecane for 48 h
proved to be necessary to finish the reaction. Careful
deprotection of the acetonide 38 with aqueous trifluoro-
acetic acid gave the diol 39.
The hydroxyl directed epoxidation using VO(acac)2
gave no epoxidation of the exocyclic double bond at room
temperature. Only after heating for 48 h in CH2Cl2 did
the starting material decompose, and no epoxide could
be detected by NMR. However, using m-CPBA in a
buffered solution yielded a 1:1 mixture of two epoxides,
and acetylation of this mixture gave dihydroclerodin (1)
(26%) and 4-epi-dihydroclerodin (41) (25%), which could
be separated easily. NMR spectroscopy and the recording
of an optical rotation of [R]D -1024 confirmed that the
natural enantiomer of dihydroclerodin had been synthe-
sized. Acetylation of diol 39 yielded the natural clerodane
lupulin C (40).25
a
Reagents: (a) O3, NaBH4; (b) NaH, CS2, MeI; (c) 216 °C; (d)
CF3CO2H; (e) Ac2O, pyridine, DMAP; (f) m-CPBA.
functional groups at C-5, C-6, and especially at C-4 is
still susceptible of improvement. It was observed that in
many transformations the yields were clearly lower
compared to similar reactions with a 1,3-dioxolan-2-yl
substituent at C-9. This may explain why the promising
results of some reactions which were described in the
literature with other substituents at C-9 did not give good
results in our compounds. The only case in which the
hexahydrofuro[2,3-b]furan moiety seems to have a ben-
eficial influence is in the final epoxidation, where a better
yield of the natural epoxide was obtained in comparison
with similar reactions in the literature.1,21
The Corey epoxidation was investigated to see whether
the selectivity of the epoxide formation could be im-
proved. For this purpose, lupulin C (40) was treated with
ozone, followed by PPh3 to yield the carbonyl group at
C-4. This ketone was submitted to a reaction with
trimethylsulfonium ylide, but during this reaction the
acetates were removed and no epoxide was obtained.
The first total synthesis of dihydroclerodin has been
achieved in an overall yield of 0.35% in 18 steps.
Characteristic for our approach is the early introduction
of the hexahydrofuro[2,3-b]furan in a remarkably dias-
tereoselective Mukaiyama reaction. In the course of this
total synthesis, the hexahydrofuro[2,3-b]furan moiety has
proven to be a stable fragment that, being an acetal,
Exp er im en ta l Section
Gen er a l Meth od s. All reagents were purchased from
Aldrich or Acros, except for carvone, which was a generous
gift of Quest International, and were used without further
purification unless otherwise stated. Melting points are uncor-
rected. Solvents were freshly distilled by common practice.
Product solutions were dried over MgSO4 prior to evaporation
of the solvent under reduced pressure by using a rotary
evaporator. For flash chromatography, Merck Kieselgel silica
60 (230-400 Mesh ASTM) was used with mixtures of ethyl
acetate and petroleum ether bp 40-60 °C as eluent (10% EA/
PE means 10 vol % of ethyl acetate in petroleum ether).
Reactions were monitored by GC with a DB-17 column (30 m
× 0.25 mm i.d.) or by TLC on silica gel plates, and visualization
of compounds was accomplished by UV detection and by
spraying with basic KMnO4 or by acidic anisaldehyde solution.
Ozone was generated by a Fisher ozone generator 502.
survived nearly all the applied reaction conditions.26
A
good solution was found for the annulation of ring A with
the correct stereochemistry at C-10 via the selective
catalytic reduction of enone 21. The introduction of the
(22) The acetonide in 32 was not very stable and decomposed in
CDCl3 during NMR recording to give a triol.
(26) It should be noted that acidic reaction conditions have to be
treated with care as was demonstrated by the isolation of compound
43 in reaction of the ozonide of 18 with PPh3 and MeOH. See also ref
18.
(23) Tschugaeff, L. (Chugaev) Chem. Ber. 1899, 32, 3332-3335.
(24) Literature [R]D -10.9 (CDCl3) [see: Beauchamp, P. S.; Bottini,
A. T.; Caselles, M. C.; Dev, V.; Hope, H.; Larter, M.; Lee, G.; Mathela,
C. S.; Melkani, A. B.; Millar, P. D.; Miyatake, M.; Pant, A. K.; Raffel,
R. J .; Sharma, V. K.; Wyatt, D. Phytochemistry 1996, 43, 827-834],
[R]D -20 (CHCl3) [see: Barton, D. H. R.; Cheung, H. T.; Cross, A. D.;
J ackman, L. M.; Martin-Smith, M. J . Chem. Soc. 1961, 5061-5073],
and [R]D -12.8 (C2H5OH) [see: Akiko, O.; Haruhisa, K.; Tsuyoshi, T.
Chem. Pharm. Bull. 1996, 44, 1540-1545].
(25) This compound is isolated from Ajuga lupulina. Chen, H.; Tan,
R. X.; Liu, Z. L.; Zhang, Y. J . Nat. Prod. 1996, 59, 668-670. However,
their reported fragment peaks are not in accordance with the ones we
found.

Total Synthesis of Dihydroclerodin
J . Org. Chem., Vol. 64, No. 25, 1999 9183
(()-cis,tr a n s-Tolu en e-4-su lfon ic a cid (2-m eth oxytet-
r a h yd r ofu r a n -3-ylm eth yl) Ester (4). To a stirred solution
of (()-cis,trans-(2-methoxytetrahydro-furan-3-yl)methanol6a
(37.5 g, 284 mmol) in pyridine (75 mL) and CHCl3 (75 mL)
was added p-toluenesulfonyl chloride (81 g, 425 mmol) in small
portions. After addition, the reaction mixture was stirred for
an additional 2 h. Then water was added, and the aqueous
phase was extracted three times with CHCl3. The combined
organic layers were washed with brine and dried. After
evaporation of the solvents, the last traces of pyridine were
removed by azeotropic distillation with toluene. The remaining
oil 4 (71 g, 249 mmol, 88%) was not purified any further: 1H
NMR (CDCl3, 200 MHz) δ 1.49 (m, 1H), 2.05 (m, 1H), 2.34 (s,
3H), 2.47 (m, 1H), 3.17 and 3.26 (s, 3H), 4.75-4.18 (m, 4H),
4.75 (d, J ) 1.1 Hz, 0.7H, trans, 4.80 (d, J ) 4.6 Hz, 0.3H, cis,
7.34 (d, J ) 8.4 Hz, 2H), 7.78 (d, J ) 8.4 Hz, 2H); 13C NMR
(CDCl3, 50 MHz) (trans) δ 21.6 (q), 26.3 (t), 44.9 (d), 54.7 (q),
65.9 (t), 70.1 (t), 105.9 (d), 127.9 (d, 2C), 129.9 (d, 2C), 132.7
(s), 145.0 (s); (cis) δ 21.6 (q), 26.3 (t), 43.2 (d), 54.4 (q), 66.4 (t),
69.4 (t), 103.1 (d), 127.9 (d, 2C), 129.9 (d, 2C), 132.7 (s), 145.0
(s).
(5R,3R)-(5-Isop r op en yl-2,3-d im et h ylcycloh ex-1-en y-
loxy)tr im eth ylsila n e27 (10): [R]20 72.7 (c 2.69, CHCl3).
D
(2R,3R,5R,2′S,3a′R,6a′S)-2-(Hexah ydr ofu r o[2,3-b]fu r an -
2′-yl)-5-isop r op en yl-2,3-d im eth ylcycloh exa n on e (11) a n d
(2R,3R,5R,2′R,3a ′S,6a ′R)-2-(Hexa h yd r ofu r o[2,3-b]fu r a n -
2′-yl)-5-isop r op en yl-2,3-d im eth ylcycloh exa n on e (12). To
a stirred solution of racemic 8 (16.0 g, 110 mmol) and 10 (22.0
g, 92.3 mmol) in CH2Cl2 (150 mL) at -78 °C was added
dropwise triphenylmethyl perchlorate28 (3.4 g, 10 mmol)
dissolved in CH2Cl2 (150 mL). The reaction mixture was stirred
for 78 h at -78 °C until 10 was not detectable anymore on
TLC (samples for monitoring the reaction were diluted using
ether with Et3N). After this period, the reaction was quenched
by addition of a saturated aqueous NaHCO3 solution (100 mL).
The aqueous phase was extracted three times with CH2Cl2.
The combined organic layers were washed with brine, dried,
and evaporated. The residue was distilled (Kugelrohr 0.01
mmHg, oven temperature 110 °C). The mixture of two dias-
tereoisomers were separated via crystallization from diisopro-
pyl ether. After two recrystallizations, the diastereoisomers
were completely separated, yielding crystalline 12 (9.1 g, 32.7
mmol, 35%) as white crystals: mp 120 °C; [R]20 65.7 (c 2.1,
D
(()-cis,tr a n s-(2-Meth oxytetr a h yd r ofu r a n -3-yl)a ceton i-
tr ile (5). To a stirred solution of 4 (70 g, 245 mmol) in DMF
(800 mL) was added NaCN (24 g, 490 mmol). The reaction
mixture was heated at 70 °C for 18 h. After this period, the
reaction mixture was poured into water (500 mL). The aqueous
phase was extracted five times with ether. The combined
organic layers were washed with brine and dried. After careful
evaporation of the solvents, the residue was distilled under
reduced pressure. First, DMF was collected at 10 mbar,
followed by 5 (28.1 g, 200 mmol, 81%) as a mixture of cis and
trans at 0.1 mbar 79-82 °C (distillation was done from a water
bath to prevent the temperature from rising above 100 °C
because above this temperature the product decomposed): 1H
NMR (CDCl3, 200 MHz) (cis) δ 1.30 (m, 1H), 2.10 (m, 1H), 2.42
(m, 3H), 3.29 (m, 3H), 3.90 (m, 2H), 4.82 (d, J ) 3.9 Hz, 1H);
13C NMR (CDCl3, 50 MHz) (cis) δ 16.8 (t), 28.9 (t), 40.4 (d),
54.8 (q), 66.6 (t), 103.4 (d), 119.1 (s); 1H NMR (CDCl3, 200 MHz)
(trans) δ 1.63 (m, 1H), 2.15-2.51 (m, 4H), 3.28 (s. 3H), 3.92
(m, 2H), 4.71 (s, 1H); 13C NMR (CDCl3, 50 MHz) (trans) δ 20.2
(t), 29.1 (t), 41.9 (d), 54.7 (q), 66.0 (t), 107.5 (d), 118.1 (s).
1
CHCl3); H NMR (CDCl3, 200 MHz) δ 0.89 (s, 3H), 0.89 (d, J
) 7.0 Hz, 3H), 1.52 (m, 1H), 1.69 (bs, 3H), 1.69 (m, 2H), 1.92-
2.16 (m, 4H), 2.33 (m, 1H), 2.55 (m, 1H), 2.71 (d, J ) 12.6 Hz,
1H), 2.82 (m, 1H), 3.87 (m, 2H), 4.63 (dd, J ) 9.6, 6.2 Hz, 1H),
4.75 (m, 2H), 5.66 (d, J ) 5.0 Hz, 1H); 13C NMR (CDCl3, 50
MHz) δ 13.4 (q), 16.7 (q), 20.4 (q), 32.6 (t), 33.0 (t), 33.1 (t),
36.8 (d), 40.4 (d), 41.9 (d), 43.3 (t), 54.3 (s), 68.0 (t), 82.6 (t),
109.0 (d), 109.4 (t), 147.4 (s), 213.4 (s).
Compound 11 (11.0 g, 39 mmol, 40%) was obtained as a
colorless oil (90% purity). A small sample was further purified
for analysis by flash chromatography (20% EA/PE): 1H NMR
(CDCl3, 200 MHz) δ 0.82 (s, 3H), 0.84 (d, J ) 5.0 Hz, 3H),
1.45 (ddd, J ) 13.4, 6.8, 5.2 Hz, 1H), 1.50-2.31 (m, 7H), 1.67
(bs, 3H), 2.48 (m, 2H), 2.80 (m, 1H), 3.87 (dd, J ) 8.6, 4.6 Hz,
2H), 4.70 (m, 3H), 5.69 (d, J ) 10.8 Hz, 1H); 13C NMR (CDCl3,
50 MHz) δ 12.8 (q), 16.7 (q), 20.5 (q), 32.6 (t), 32.9 (t), 33.0 (t),
36.2 (d), 40.5 (d), 42.6 (d), 44.8 (t), 56.0 (s), 67.8 (t), 80.3 (d),
109.5 (d), 109.7 (t), 147.4 (s), 213.2 (s).
(1R,2S,3R,5R,2′S,3a ′R,6a ′S)-2-(Hexa h yd r ofu r o[2,3-b]fu -
r an -2′-yl)-5-isopr open yl-2,3-dim eth yl-1-cycloh exan ol (13).
To a stirred solution of 11 (0.94 g, 3.4 mmol) in THF (30 mL)
was added dropwise lithium tri-sec-butylborohydride (1 M in
THF, 5 mL) at -78 °C. The reaction mixture was allowed to
come to room temperature and stirred for an additional 8 h.
After this period, the reaction mixture was cooled to -10 °C,
and an aqueous solution of NaOH (1 M, 10 mL) and an
aqueous solution of H2O2 (30%, 8 mL) were added slowly,
followed by 2 h vigorous stirring. Water (20 mL) was added,
and then the aqueous phase was extracted three times with
ether. The combined organic layers were carefully washed with
an aqueous solution of Na2SO3 and brine, dried, and evapo-
rated. The residue was purified by flash chromatography (30%
EA/PE) to give 13 (0.91 g, 3.25 mmol, 96%) as a colorless oil:
1H NMR (CDCl3, 200 MHz) δ 0.90 (s, 3H), 0.99 (d, J ) 7.4 Hz,
3H), 1.38 (m, 1H), 1.60-2.40 (m, 10H), 1.76 (bs, 3H), 2.78 (m,
1H), 3.71 (dd, J ) 10.2, 5.1 Hz, 1H), 3.88 (m, 2H), 4.41 (dd, J
(()-Tetr a h yd r ofu r o[2,3-b]fu r a n -2-on e (7). A well-stirred
emulsion of 5 (9.6 g, 68.0 mmol) in an aqueous solution of
NaOH (5 M, 20 mL) was refluxed for 2.5 h until a clear solution
was formed. The reaction mixture was cooled to room tem-
perature, followed by washing of the aqueous phase with 25
mL of ether. Then the aqueous phase was acidified with
concentrated HCl until pH 1 and stirred for an additional 1.5
h. Then the aqueous phase was extracted five times with ethyl
acetate. The combined organic layers were washed with brine
and dried. After careful evaporation of the solvents, the residue
was distilled under reduced pressure (Kugelrohr 0.2 mmHg,
oven temperature 80 °C) to give 8 (7.89 g, 61.6 mmol, 91%).
1H NMR spectra were in accordance with the literature.10
(()-2-Meth oxyh exah ydr ofu r o[2,3-b]fu r an (8). To a stirred
solution of 711 (10.0 g, 78 mmol) in dry toluene (40 mL) was
slowly added DIBALH (1.5 M in toluene, 55 mL, 82 mmol) at
-78 °C. After addition, the reaction mixture was stirred for
an additional 1.5 h at -78 °C and then quenched by adding
dry MeOH (2.9 g, 90 mmol) together with BF3‚etherate (21
mL, 167 mmol) as quickly as possible without raising the
temperature above -60 °C (>10 min). The reaction mixture
was stirred for an additional 5 min and then poured into a
large beaker with water (100 mL) and NaHCO3 (50 g, 0.6 mol).
The resulting slurry was stirred for 2 h, allowing the NaHCO3
to react with the excess of BF3‚etherate. After this period, the
aqueous phase was extracted three times with ether. The
combined organic layers were washed with brine and dried.
After careful evaporation of the solvents, a colorless oil was
distilled (Kugelrohr 3 mmHg, oven temperature 80 °C) and
afforded 8 (7.0 g, 49 mmol, 62%) as a 1:2 mixture of diaste-
reoisomers, along with 1.1 g of the overreduced hexahydrofuro-
[2,3-b]furan. Further purification was not necessary. NMR
spectra were in accordance with the literature.10
) 10.7, 5.5 Hz, 1H), 4.76 (m, 2H), 5.65 (d, J ) 5.1 Hz, 1H); 13
C
NMR (CDCl3, 50 MHz) δ 16.4 (q), 16.5 (q), 21.0 (q), 32.8 (t),
33.1 (d), 33.4 (t), 34.6 (t), 35.2 (t), 38.2 (d), 42.1 (s), 42.4 (d),
68.3 (t), 74.1 (d), 80.1 (d), 107.9 (d), 108.9 (t), 149.7 (s).
(3S,4R,6R,2′S,3a ′R,6a ′S)-3-(Hexa h yd r ofu r o[2,3-b]fu r a n -
2′-yl)-6-isop r op en yl-3,4-d im eth ylcycloh exen e (14). To a
stirred solution of 13 (0.91 g, 3.25 mmol) in pyridine (5 mL)
and CH2Cl2 (5 mL) was added MsCl (0.6 mL, 5 mmol) at 0 °C.
The reaction mixture was stirred overnight, followed by
addition of water (50 mL). The aqueous phase was extracted
three times with CH2Cl2. The combined organic layers were
washed with brine, dried, and evaporated. The residue was
(27) Verstegen-Haaksma, A. A.; Swarts, H. J .; J ansen, B. J . M.; de
Groot, A. Tetrahedron 1994, 50, 10073-10082.
(28) Dauben, H. J .; Honnen, L. R.; Harmon, K. M. J . Org. Chem.
1960, 25, 1442-1445.

9184 J . Org. Chem., Vol. 64, No. 25, 1999
Meulemans et al.
purified by flash chromatography (30% EA/PE) to give the
mesylate (0.49 g, 1.37 mmol, 42%) as a colorless oil.
(s); MS m/z (relative intensity) 113 (100); HRMS calcd for
C20H24O3S (M+) 344.1446, found 344.1445 (σ ) 0.12 mmu).
(4S,5R,2′S,3a ′R,6a ′S)-4-(Hexa h yd r ofu r o[2,3-b]fu r a n -2′-
yl)-4,5-d im eth ylcycloh ex-2-en on e (17). To a stirred suspen-
sion of LiAlH4 (1.0 g, 26.3 mmol) in dry ether (150 mL) was
added 16 (8.3 g, 24.1 mmol) dissolved in dry ether (50 mL).
The reaction mixture was stirred for 30 min at room temper-
ature. After this period, water (50 mL) was added. The aqueous
phase was extracted three times with ether. The combined
organic layers were washed with brine, dried, and evaporated.
The residue was dissolved in CHCl3 (100 mL), followed by
addition of PTSA (0.5 g). The reaction mixture was stirred
overnight. After this period, CHCl3 (100 mL) was added, and
the mixture was washed twice with an aqueous solution of
NaOH (4 M, 10 mL) and brine (10 mL), dried, and evaporated.
The residue was purified by flash chromatography (30% EA/
PE) to give 17 (4.2 g, 17.8 mmol, 74%) as white crystals: mp
90 °C; [R]20D -12.6 (c 3.02, CHCl3); 1H NMR (CDCl3, 200 MHz)
δ 0.94 (d, J ) 6.6 Hz, 3H), 1.13 (s, 3H), 1.61-1.75 (m, 3H),
1.98-2.30 (m, 4H), 2.84 (m, 1H), 3.88 (m, 2H), 4.17 (dd, J )
9.9, 6.5 Hz, 1H), 5.73 (d, J ) 5.0 Hz, 1H) 5.97 (d, J ) 10.3 Hz,
1H), 6.89 (d, J ) 10.3 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ
15.5 (q), 16.4 (q), 32.8 (t), 34.3 (d), 34.7 (t), 42.0 (t), 42.4 (d),
42.5 (s), 68.4 (t), 83.1 (d), 109.0 (d), 129.1 (d), 155.1 (d), 199.5
(s). Anal. Calcd for C14H20O3: C, 71.16; H, 8.53. Found: C,
71.09; H, 8.57.
To a solution of the mesylate (400 mg, 1.12 mmol) in dry
DMF (20 mL) were added LiBr (0.5 g) and Li2CO3 (0.5 g). The
reaction mixture was heated at 100 °C for 36 h, cooled to room
temperature, and poured into water (20 mL). The aqueous
phase was extracted thee times with petroleum ether. The
combined organic layers were washed two times with brine,
dried, and evaporated. The residue was purified by flash
chromatography (5% EA/PE) to give 14 (290 mg, 1.24 mmol,
90%) as white crystals. For X-ray analysis, the crystals
were recrystallized from hexanes to afford almost colorless
needles: mp 68-70 °C; [R]20 114 (c 3.3, CHCl3); 1H NMR
D
(CDCl3, 200 MHz) δ 0.81 (d, J ) 6.3 Hz, 3H), 0.96 (s, 3H),
1.35-2.18 (m, 7H), 1.72 (s, 3H), 2.61 (m, 1H), 2.77 (m, 1H),
3.86 (m, 2H), 4.12 (dd, J ) 10.2, 5.9 Hz, 1H), 4.63 (bs, 1H),
4.77 (bs, 1H), 5.60 (s, 2H), 5.68 (d, J ) 5.0 Hz, 1H); 13C NMR
(CDCl3, 50 MHz) δ 15.9 (q), 18.3 (q), 22.1 (q), 29.4 (d), 30.7 (t),
32.9 (t), 34.0 (t), 41.2 (d), 41.2 (s), 42.4 (d), 68.1 (t), 84.9 (d),
109.0 (d), 111.2 (t), 129.3 (d), 132.5 (d), 148.2 (s); MS m/z
(relative intensity) 113 (100); HRMS calcd for C17H26O2 (M+)
262.1932, found 262.1932 (σ ) 0.057 mmu).
(5R,6R,2′S,3a ′R,6a ′S)-6-(Hexa h yd r ofu r o[2,3-b]fu r a n -2′-
yl)-5,6-d im eth ylcycloh ex-2-en on e (15). A stirred solution
of 11 (12.5 g, 45 mmol) in CH2Cl2 (300 mL) and MeOH (250
mL) at -78 °C was purged through with ozone until a pale
blue color appeared. Then nitrogen was purged through to
remove the excess of ozone, followed by addition of FeSO4‚7H2O
(12.5 g, 45 mmol) and Cu(OAc)2‚H2O (17.7 g, 90 mmol). The
reaction mixture was allowed to come to room temperature
and stirred overnight. After this period, the reaction mixture
was concentrated to 100 mL, followed by addition of aqueous
HCl (4 M, 150 mL). The aqueous phase was extracted three
times with ether. The combined organic layers were washed
with an aqueous solution of NaOH (4 M) and brine, dried, and
evaporated. The residue was purified by flash chromatography
(3R,4S,5R,2′S,3a ′R,6a ′S)-4-(Hexa h yd r ofu r o[2,3-b]fu r a n -
2′-yl)-4,5-d im eth yl-3-p en t-4-en ylcycloh exa n on e (18). To a
stirred solution of CuBr‚Me2S (1.5 g, 7.3 mmol) in THF (80
mL) and HMPA (5 mL) was added dropwise a freshly prepared
solution of pent-4-enylmagnesium bromide in ether (50 mL,
30 mmol) at -78 °C. The reaction mixture was stirred for 1.5
h at -78 °C, followed by addition of 17 (1.82 g, 7.71 mmol)
dissolved in THF (20 mL) and TMSCl (2 mL). The reaction
mixture was stirred for 5 h. After this period, water (10 mL)
was added slowly, followed by an aqueous solution of HCl (4
M, 20 mL). The aqueous phase was extracted three times with
ether. The combined organic layers were washed with brine,
dried, and evaporated. The residue was purified by flash
chromatography (30% EA/PE) to give 18 (2.07 g, 6.76 mmol,
(30% EA/PE) to give 15 (7.3 g, 31 mmol, 70%) as a colorless
1
oil: [R]20 -36.5 (c 2.55, CHCl3); H NMR (CDCl3, 200 MHz)
D
δ 0.91 (s, 3H), 0.95 (d, J ) 4.7 Hz, 3H), 1.38 (ddd, J ) 13.4,
6.8, 3.1 Hz, 1H), 1.65 (m, 1H), 1.89-2.17 (m, 3H), 2.48 (m,
1H), 2.88 (m, 2H), 3.82 (m, 2H), 4,45 (dd, J ) 8.8, 6.6 Hz, 1H),
5.67 (d, J ) 5.0 Hz, 1H), 5.88 (ddd, J ) 10.0, 2.8, 1.2 Hz, 1H),
6.77 (dddd, J ) 10.0, 5.3, 2.8, 1.4 Hz, 1H); 13C NMR (CDCl3,
50 MHz) δ 12.6 (q), 16.3 (q), 31.7 (t), 32.8 (t), 33.0 (t), 34.8 (t),
42.6 (d), 53.0 (s), 67.7 (t), 80.0 (d), 109.6 (d), 128.8 (d), 147.7
(d), 202.2 (s); MS m/z (relative intensity) 124 (100), 113 (90);
HRMS calcd for C14H20O3 (M+) 236.1412, found 236.1413 (σ )
0.083 mmu).
88%) as white crystals: mp 109 °C; [R]20 -24.0 (c 1.03,
D
1
CHCl3); H NMR (CDCl3, 200 MHz) δ 0.88 (s, 3H), 0.95 (d, J
) 6.8 Hz, 3H), 1.11-1.20 (m, 2H), 1.38-1.78 (m, 5H), 1.90-
2.25 (m, 6H), 2.41 (d, J ) 6.6 Hz, 2H), 2.62 (dd, J ) 14.4, 4.8
Hz, 1H), 2.78 (m, 1H), 3.85 (m, 2H), 4.17 (dd, J ) 11.1, 5.2
Hz, 1H), 4.94 (m, 2H), 5.65 (d, J ) 5.3 Hz, 1H), 5.76 (m, 1H);
13C NMR (CDCl3, 50 MHz) δ 17.2 (q), 17.8 (q), 26.9 (t), 28.3
(t), 32.6 (t), 33.6 (t), 34.0 (t), 35.9 (d), 40.1 (s), 41.4 (d), 42.5 (t),
43.6 (d), 46.6 (t), 68.3 (t), 83.9 (d), 108.6 (d), 114.7 (t), 138.4
(d), 212.9 (s). Anal. Calcd for C19H30O3: C, 74.47; H, 9.87.
Found: C, 73.52; H, 9.92.
(3R ,4S ,4a S ,2′S ,3a ′R ,6a ′S )-3,4,4a ,5,6,7-H e xa h yd r o-4-
(h exa h yd r ofu r o[2,3-b]fu r a n -2′-yl)-3,4-d im eth yl-2H-n a p h -
th a len -1-on e (19). A solution of 18 (2.1 g, 6.76 mmol) in
CH2Cl2 (80 mL) at -78 °C was purged through with ozone until
a pale blue color appeared. Then nitrogen was purged through,
followed by addition of Ph3P (2.1 g, 8.0 mmol). The reaction
mixture was allowed to come to room temperature and stirred
overnight. Then the solvent was evaporated. The residue was
purified by flash chromatography (60% EA/PE) to give
(1R,2S,3R,2′S,3a ′R,6a ′S)-4-(4-(h exa h yd r ofu r o[2,3-b]fu r a n -
2′-yl)-2,3-d im eth yl-5-oxocycloh exyl)bu tyr a ld eh yd e (1.87
g, 6.1 mmol, 90%) as white crystals: 1H NMR (CDCl3, 200
MHz) δ 0.86 (s, 3H), 0.92 (d, J ) 6.7 Hz, 3H), 1.06-2.22 (m,
11H), 2.39 (m, 4H), 2.59 (dd, J ) 14.2, 4.6 Hz, 1H), 2.76 (m,
1H), 3.82 (m, 2H), 4.11 (dd, J ) 11.1, 5.2 Hz, 1H), 5.62 (d, J )
5.1, 1H), 9.67 (bs, 1H).
(5R,6R,2′S,3a ′R,6a ′S)-6-(Hexa h yd r ofu r o[2,3-b]fu r a n -2′-
yl)-5,6-d im eth yl-3-p h en ylsu lfa n ylcycloh ex-2-en on e (16).
To a stirred solution of 15 (10.4 g, 43.8 mmol) in pentane (300
mL) and THF (100 mL) were added thiophenol (5.5 g, 50 mmol)
and Et3N (1 mL). The reaction mixture was stirred for 27 h,
followed by evaporation of the solvents. The residue was
purified by flash chromatography (first 10% EA/PE, then 30%
EA/PE) to give a mixture of the R- and â-phenyl sulfide (11.02
g, 31.8 mmol, 73%) as a colorless and slightly smelly oil. This
mixture (9.0 g, 26 mmol) was dissolved in ether (100 mL) and
benzene (100 mL), and trichloroisocyanuric acid (2.0 g, 8.67
mmol) was added in three portions within 5 min, at 0 °C (ice-
salt bath). The reaction mixture was stirred for no more than
5 min. Then K2CO3 (5 g) was added, followed by filtration over
silica. The solvents were evaporated under reduced pressure
at 0 °C. The residue was purified by flash chromatography
(20% EA/PE) to give 16 (8.3 g, 24.1 mmol, 93%) as a colorless
oil: 1H NMR (CDCl3), 200 MHz) δ 0.91 (s, 3H), 0.96 (d, J )
4.6 Hz, 3H), 1.40 (ddd, J ) 13.4, 6.8, 3.4 Hz, 1H), 1.65 (m,
1H), 2.02-1.93 (m, 2H), 2.21 (dd, J ) 18.3, 2.8 Hz, 1H), 2.54
(m, 1H), 2.81 (m, 1H), 3.09 (ddd, J ) 18.3, 5.1, 2.1 Hz, 1H),
3.87 (m, 2H), 4.44 (dd, J ) 8.3, 6.9 Hz, 1H), 5.40 (d, J ) 2.1
Hz, 1H), 5.69 (d, J ) 5.0 Hz, 1H), 7.40 (m, 5H); 13C NMR
(CDCl3, 50 MHz) δ 12.9 (q), 16.2 (q), 32.7 (t), 32.8 (t), 35.0 (d),
35.1 (t), 42.5 (d), 52.0 (s), 67.6 (t), 80.1 (d), 109.5 (d), 119.8 (d),
128.0 (s), 129.7 (d, 2C), 130.0 (d, 2C), 135.4 (d), 163.6 (s), 198.1
A solution of the aldehyde (0.9 g, 2.9 mmol) in benzene (40
mL) and PPTS (50 mg) was refluxed using a Dean-Stark
apparatus for 4 h. The reaction mixture was cooled, followed
by addition of a saturated aqueous NaHCO3 solution (10 mL).
The aqueous phase was extracted three times with ether. The
combined organic layers were washed with brine, dried, and
evaporated. The residue was purified by flash chromatography
(20% EA/PE) to give 19 (0.53 g, 1.8 mmol, 63%) as a colorless

Total Synthesis of Dihydroclerodin
J . Org. Chem., Vol. 64, No. 25, 1999 9185
1
oil: [R]20 -35.1 (c 1.50, CHCl3); H NMR (C6D6, 400 MHz) δ
(3R ,4S ,4a R ,2′S ,3a ′R ,6a ′S )-3,4,4a ,5,6,7-H e xa h yd r o-4-
(h exa h yd r ofu r o[2,3-b]fu r a n -2′-yl)-3,4-d im eth yl-2H-n a p h -
th a len -1-on e (23). A solution of THF (25 mL), water (20 mL),
PPTS (0.5 g), and 22 (1.5 g, 4.3 mmol) was refluxed for 12 h
and then cooled to room temperature, followed by addition of
a saturated aqueous NaHCO3 solution (3 mL). After the THF
was evaporated, the aqueous phase was extracted three times
with ethyl acetate. The combined organic layers were washed
with brine, dried, and evaporated. The residue was treated
with PPTS as described for compound 19 yielding 23 (0.78 g,
2.68 mmol, 63%) as a colorless oil: [R]20D -52.7 (c 1.0, CHCl3);
1H NMR (C6D6, 400 MHz) δ 0.70 (d, J ) 6.8 Hz, 3H), 0.85 (s,
3H), 1.22 (ddd, J ) 12.8, 5.6, 1.5 Hz, 1H), 1.27-1.41 (m, 2H),
1.57-1.82 (m, 5H), 1.95 (m, 2H), 2.07 (m, 1H), 2.14 (dd, J )
17.5, 10.8 Hz, 1H), 2.42, (m, 1H), 2.48 (dd, J ) 17.5, 5.9 Hz,
1H) 2.59 (m, 1H), 3.72 (m, 2H), 4.12 (dd, J ) 11.2, 5.6 Hz,
1H), 5.69 (d, 5.0 Hz, 1H), 7.22 (m, 1H); 13C NMR (C6D6, 100
MHz) δ 12.3 (q), 17.4 (q), 22.4 (t), 24.1 (t), 24.9 (t), 33.0 (d),
40.5 (s), 42.5 (d), 42.6 (d), 44.8 (t), 68.3 (t), 84.1 (t), 108.6 (d),
138.0 (s), 138.3 (d), 198.0 (s).
D
0.75 (s, 3H), 0.93 (d, J ) 6.8 Hz, 3H), 1.20-1.30 (m, 2H), 1.37
(m, 1H) 1.50-1.76 (m, 5H), 1.98-2.05 (m, 2H), 2.13 (ddq, J )
7.1, 2.6, 7.1 Hz, 1H), 2.33 (m, 1H), 2.33 (dd, J ) 17.5, 2.7 Hz,
1H), 2.43 (ddd, J ) 14.8, 7.5, 3.8 Hz, 1H), 3.10 (dd, J ) 17.5,
6.1 Hz, 1H), 3.64 (m, 2H), 4.12 (dd, J ) 10.8, 5.4 Hz, 1H), 5.60
(d, J ) 5.1 Hz, 1H), 7.15 (m, 1H); 13C NMR (C6H6, 100 MHz)
δ 17.7 (q), 20.9 (q), 23.1 (t), 24.2 (t), 26.3 (t), 33.1 (t), 33.6 (d),
34.5 (t), 39.3 (s), 41.8 (d), 42.3 (d), 44.2 (t), 68.2t, 82.9 (d), 108.4
(d), 135.5 (d), 138.0 (s), 198.0 (s); MS m/z (relative intensity)
113 (100); HRMS calcd for C18H26O3 (M+) 290.1882, found
290.1881 (σ ) 0.09 mmu).
(4S,5R,2′S,3a ′R,6a ′S)-3-(3-[1,3]Dioxola n -2-ylp r op yl)-4-
(h exa h yd r ofu r o[2,3-b]fu r a n -2′-yl)-4,5-d im eth ylcycloh ex-
2-en on e (21). A solution of 3-(1,3-dioxolan-2-yl)propyllithium
was prepared by adding t-BuLi (1.5M in pentane, 33 mL, 49.5
mmol) to a degassed solution of 2-(3-iodopropyl)[1,3]dioxolane29
(6.0 g, 24.8 mmol) in dry ether (80 mL) at -78 °C under argon.
The temperature was allowed to rise to room temperature, and
the reaction mixture was stirred for an additional 45 min. The
fresh prepared lithium reagent was added to a stirred solution
of 15 (4.0 g, 17 mmol) in dry ether (80 mL) at -78 °C. After
addition, the reaction mixture was stirred for an additional 3
h at -78 °C and then quenched with water (30 mL). The
aqueous phase was extracted three times with ethyl acetate,
and the combined organic layers were washed with brine,
dried, and evaporated. The residue was dissolved in CH2Cl2
(100 mL) and DMF (4 mL), followed by addition of PCC (8.0
g, 37 mmol) in three portions at 0 °C. The reaction mixture
was stirred overnight at room temperature. After this period,
ether (200 mL) was added and the reaction mixture was
filtered over a short path of silica. The filter was washed
extensively, followed by evaporation of the solvents. The
residue was purified by flash chromatography (first 20% EA/
PE, then 60% EA/PE) to give (5R,6R,2′S,3a ′R,6a ′S)-6-
(Hexa h yd r ofu r o[2,3-b]fu r a n -2′-yl)-5,6-d im eth ylcycloh ex-
3-en on e (1.0 g, 4.2 mmol, 25%) as a colorless oil: 1H NMR
(CDCl3, 200 MHz) δ 086 (d, J ) 4.8 Hz, 3H), 0.91 (s, 3H), 1.47
(ddd, J ) 13.2, 6.9, 3.3 Hz, 1H), 1.58-2.12 (m, 4H), 2.74 (m,
2H), 2.84 (m, 1H), 3.85 (m, 2H), 4.75 (dd, J ) 8.6, 6.9 Hz, 1H),
5.58 (m, 1H), 5.65 (d, J ) 4.9 Hz, 1H), 5.77 (m, 1H); 13C NMR
(CDCl3, 50 MHz) δ 11.6 (q), 17.2 (q), 32.9 (t), 33.3 (t), 39.4 (t),
40.5 (d), 42.7 (d), 56.2 (s), 67.7 (t), 80 4 (d), 109.4 (d), 121.7
(d), 133.1 (d), 211.2 (s); MS m/z (relative intensity) 166 (15),
151 (11), 124 (16), 113 (100); HRMS calcd for C14H20O3 (M+)
236.1412, found 236.1410 (σ ) 0.059 mmu).
(3R,4S,4a S,8R,8a S,2′S,3a ′R,6a ′S)-8a -(ter t-Bu tyld im eth -
ylsila n yloxym eth yl)-4-(h exa h yd r ofu r o[2,3-b]fu r a n -2′-yl)-
3,4-d im eth ylocta h yd r o-8-vin yln a p h th a len -1-on e (26). To
a degassed solution of CuBr‚Me2S (100 mg, 0.5 mmol), HMPA
(0.3 mL), and dry THF (20 mL) under argon was added
vinylMgBr (1 M in THF, 2.5 mL, 2.5 mmol) at -78 °C. The
reaction mixture was stirred for 1.5 h at -78 °C, followed by
addition of 23 (237 mg, 0.82 mmol) dissolved in THF (3 mL).
After addition, the reaction mixture was stirred for an ad-
ditional 1 h. Then a freshly prepared oxygen free solution of
formaldehyde in THF (15 mL) was added quickly.30 Stirring
was continued for no more than 10 min. Then the reaction
was quenched in an aqueous NH4Cl solution (60 mL), followed
by vigorous extraction with ethyl acetate (three times). The
combined organic layers were washed with brine, dried, and
evaporated. The residue was dissolved in DMF (5 mL), tert-
butyldimethylsilyl chloride (0.3 g, 2.0 mmol) and a trace of
imidazole. The reaction mixture was stirred for 12 h at room
temperature. After this period, water (10 mL) was added, and
the aqueous phase was extracted three times with ether. The
combined organic layers were washed with brine, dried, and
evaporated. The residue was purified by flash chromatography
(20% EA/PE) to give 26 (190 mg, 0.41 mmol, 51%): [R]20D 89.5
1
(c 2.95, CHCl3); H NMR (CDCl3, 200 MHz) δ -0.01 (s, 3H),
0.01 (s, 3H), 0.84 (s, 9H), 0.88 (d, J ) 7.1 Hz, 3H), 0.96 (s,
3H), 1.40-2.42 (m, 14H), 2.82 (m, 1H), 2.97 (m, 1H), 3.86 (m,
2H), 3.95 (s, 2H), 4.20 (dd, J ) 11.6, 5.8 Hz, 1H), 5.03 (m, 2H),
5.63 (d, J ) 5.1 Hz, 1H), 5.90 (ddd, J ) 17.1, 9.8, 6.8 Hz, 1H);
13C NMR (CDCl3, 50 MHz) δ -5.7 (q, 2C), 15.4 (q), 17.9 (q),
18.3 (s), 21.4 (t), 22.5 (t), 22.6 (t), 22.8 (q, 3C), 32.8 (t, 2C),
33.8 (d), 40.0 (s), 41.2 (d), 42.2 (d), 42.3 (d), 46.2 (t), 56.2 (s),
63.9 (t), 68.2 (t), 85.9 (d), 108.5 (d), 116.2 (t), 138.8 (d), 213.1
(s); MS m/z (relative intensity) 405 (11), 113 (100); HRMS calcd
for C23H37O4Si (M+-57) 405.2461, found 405.2460 (σ ) 0.113
mmu).
Followed by 21 (2.5 g, 7.1 mmol, 42%) as a colorless oil:
[R]20 43.2 (c 2.57, CHCl3); H NMR (CDCl3, 200 MHz) δ 089
1
D
(d, J ) 6.9 Hz, 3H), 1.02 (s, 3H), 1.3-2.3 (m H), 2.68-2.89 (m,
3H), 3.77-3.92 (m, 6H), 4.12 (dd, J ) 10.6, 5.6 Hz, 1H), 4.79
(t, J ) 4.0 Hz, 1H) 5.60 (d, J ) 5.0 Hz, 1H), 5.86 (bs, 1H); IR
1666 cm-1
.
(3S,4S,5R,2′S,3a ′R,6a ′S)-3-(3-[1,3]Dioxola n -2-ylp r op yl)-
4-(h exa h yd r ofu r o[2,3-b]fu r a n -2′-yl)-4,5-d im et h ylcyclo-
h exa n on e (22). To a stirred suspension of Pd/C (10%) (690
mg) in THF (100 mL) saturated with hydrogen was added a
solution of 21 (2.7 g, 7.7 mmol) in THF. The reaction mixture
was stirred under hydrogen for 20 h. Then the Pd/C was
filtered and washed with ethyl acetate. The solvents were
evaporated, and the residue was purified by flash chromatog-
raphy (60% EA/PE) to give 22 (2.2 g, 6.2 mmol, 81%) as a
colorless oil: 1H NMR (CDCl3, 200 MHz) δ 088 (d, J ) 6.8 Hz,
3H), 0.99 (s, 3H), 1.38-2.26 (m, 15H), 2.39 (dd, J ) 14.8, 3.9
Hz, 1H), 2.85 (m, 1H), 3.82 (m, 6H), 4.22 (dd, J ) 11.1, 5.7
(1S,3R,4S,4a S,8S,8a R,2′S,3a ′R,6a ′S)-Acetic Acid 1-Ac-
etoxy-8-for m yld eca h yd r o-4-(h exa h yd r ofu r o[2,3-b]fu r a n -
2′-yl)-3,4-d im eth yln a p h th a len -8a -ylm eth yl Ester (27). To
a stirred solution of 26 (94 mg, 21 mmol) in ether (25 mL)
was added LiAlH4 (50 mg) at 0 °C. The reaction mixture was
stirred for 3 h at room temperature. After this period, ice-
water (5 mL) was added, followed by an aqueous solution of
HCl (2 M, 10 mL). The aqueous phase was extracted three
times with ethyl acetate. The combined organic layers were
washed with brine, dried, and evaporated to yield the crude
diol. A solution of the crude diol in pyridine (5 mL), acetic
anhydride (1 mL), and a trace of DMAP was stirred overnight.
Then water was added, and the aqueous phase was extracted
three times with ether. The combined organic layers were
washed with brine, dried, and evaporated. The residue was
purified by flash chromatography (30% EA/PE) to give
Hz, 1H), 4.79 (t, J ) 4.4 Hz, 1H), 5.63 (d, J ) 5.1 Hz, 1H); 13
C
NMR (CDCl3, 50 MHz) δ 11.7 (q), 17.2 (q), 22.1 (t), 30.6 (t),
32.3 (t), 32.8 (t), 33.9 (t), 36.5 (d), 40.3 (s), 41.4 (d), 42.1 (d),
42.7 (t), 46.0 (t), 64.8 (t, 2C), 68.3 (t), 84.7 (d), 104.3 (d), 108.2
(d), 211.5 (s); MS m/z (relative intensity) 113 (100); HRMS
calcd for C20H32O5 (M+) 352.2250, found 352.2246 (σ ) 0.026
mmu); IR 1717 cm-1
.
(30) Schlosser, M.; J enny, T.; Guggisberg, Y. Synlett 1990, 704. For
oxygen free, a cooled solution of THF, paraformaldehyde, and acid was
degassed prior to slowly distillation under argon.
(29) Pleshakov, M. G.; Vasil’ev, A. E.; Sarycheva, I. K.; Preobrazhen-
skii, N. A. J . Gen. Chem. U.S.S.R. 1961, 31, 1433-1435.

9186 J . Org. Chem., Vol. 64, No. 25, 1999
Meulemans et al.
(1S,3R,4S,4a S,8R,8a S,2′S,3a ′R,6a ′S)-Acet ic a cid 1-Ace-
t oxyd eca h yd r o-4-(h exa h yd r ofu r o[2,3-b]fu r a n -2′-yl)-3,4-
d im eth yl-8-vin yln a p h th a len -8a -ylm eth yl ester (67 mg,
0.15 mmol, 71%): 1H NMR (CDCl3, 200 MHz) δ 0.81 (d, J )
6.2 Hz, 3H), 0.91 (s, 3H), 1.30-2.15 (m, 14H), 1.90 (s, 3H),
2.03 (s, 3H), 2.80 (m, 2H), 3.73 (m, 2H), 4.04 (dd, J ) 11.3, 5.4
Hz, 1H), 4.16 (d, J ) 12.3 Hz, 1H), 4.48 (dd, J ) 9.8, 4.9 Hz,
1H), 4.87 (d, J ) 12.3 Hz, 1H), 4.91 (dd, J ) 16.7, 2.2 Hz, 1H),
5.04 (dd, J ) 10.1, 2.2 Hz, 1H), 5.57 (d, J ) 5.1 Hz, 1H), 6.14
(ddd, J ) 16.7, 10.1, 10.1 Hz, 1H); 13C NMR (CDCl3, 50 MHz)
δ 15.0 (q), 16.5 (q), 20.9 (t), 21.1 (q), 21.2 (q), 22.4 (t), 27.2 (t),
31.9 (t), 32.5 (t, 2C), 35.9 (d), 40.3 (s), 41.4 (d), 41.5 (d), 42.1
(d), 43.9 (s), 61.3 (t), 68.3 (t), 77.0 (d), 85.9 (d), 107.7 (d), 117.3
(t), 137.7 (d), 170.1 (s), 170.7 (s); MS m/z (relative intensity)
113 (100); HRMS calcd for C25H38O6 (M+) 434.2668, found
434.2659 (6 scans), calcd for C17H24O2 (M+-174) 260.1776, found
260.1774 (σ ) 0.096 mmu).
168.7 (s); MS m/z (relative intensity) 113 (100); HRMS calcd
for C16H23O379Br (M+ - 130) 342.0831, found 342.0823 (σ )
0.149 mmu).
(4a S,6R,7S,7a R,11R,2′S,3a ′R,6a ′S)-7-(H exa h yd r ofu r o-
[2,3-b ]fu r a n -2′-y l)-3,3,6,7-t e t r a m e t h y lo c t a h y d r o -11-
vin yln a p h th o[1,8a -d ][1,3]d ioxin e (31). Reduction of com-
pound 26 was done as described for compound 27. To a stirred
solution of the crude diol (234 mg, 0.68 mmol) in dry DMF (5
mL) and 2,2-dimethoxypropane (5 mL) was added a crystal of
PPTS. The reaction mixture was stirred for 0.5 h, followed by
addition of a saturated aqueous NaHCO3 solution (5 mL) and
water (5 mL). The aqueous phase was extracted three times
with ether. The combined organic layers were washed with
brine, dried, and evaporated. The residue was purified by flash
chromatography (20% EA/PE) to give 31 (175 mg, 0.45 mmol,
1
66%): [R]20 8.8 (c 1.0, CHCl3); H NMR (C6D6, 200 MHz) δ
D
0.85 (d, J ) 5.8 Hz, 3H), 0.96 (s, 3H), 1.05-1.18 (m, 3H), 1.41
(s, 6H), 1.30-2.05 (m, 11H), 2.22 (m, 1H), 3.13 (m, 1H), 3.56
(m, 2H), 3.76 (d, J ) 12.1 Hz, 1H), 3.84 (dd, J ) 8.9, 4.2 Hz,
1H), 3.96 (dd, J ) 11.2, 5.3 Hz, 1H), 4.04 (d, J ) 12.1 Hz, 1H),
5.06 (dd, J ) 10.0, 2.5 Hz, 1H), 5.21 (dd, J ) 16.8, 2.5 Hz,
1H), 5.57 (d, J ) 5.0 Hz, 1H), 6.12 (ddd, J ) 16.8, 10.0, 10.0
Hz, 1H); 13C NMR (C6D6, 50 MHz) δ 15.5 (q), 18.7 (q), 21.8 (t),
22.6 (t), 26.7 (q), 26.9 (q), 27.4 (t), 32.6 (t, 2C), 32.7 (d), 34.8
(t), 40.1 (d), 40.5 (d), 41.8 (s), 42.0 (d), 44.7 (d), 61.1 (t), 67.9
(t), 73.5 (d), 85 3 (d), 98.6 (s), 108.2 (d), 116.8 (t), 138.9 (d).
(2*,2a *,5a R,6S,7R,8a S,8bR,2′S,3a ′R,6a ′S)-8b-Hyd r oxy-
m eth yl-d eca h yd r o-6-(h exa h yd r o-fu r o[2,3-b]fu r a n -2′-yl)-
6,7-d im et h yl-n a p h t h o[1,8-bc]fu r a n -2-ol (30). Compound
31 (20 mg, 5.1 × 10-5 mol) was ozonized as described for
compound 19 yielding (4a S,6R,7S,7a R,11S,2′S,3a ′R,6a ′S)-
7-(Hexa h yd r ofu r o[2,3-b]fu r a n -2′-yl)-3,3,6,7-tetr a m eth yl-
o c t a h y d r o n a p h t h o [1,8a -d ][1,3]d io x in e -11-c a r b a ld e -
h yd e (18.7 mg, 4.8 × 10-5 mol, 93%) as a white gum, which
A solution of this vinyldiacetate (67 mg, 0.15 mmol) was
ozonized as described for compound 19 to give 27 (64 mg, 0.15
1
mmol, 95%): [R]20 -26.2 (c 3.0, CHCl3); H NMR (C6D6, 200
D
MHz) δ 0.59 (d, J ) 6.7 Hz, 3H), 0.92 (s, 3H), 1.05-1.78 (m,
11H), 1.70 (s, 3H), 1.74 (s, 3H), 2.11-2.46 (m, 3H), 2.98 (m,
1H), 3.59 (m, 2H), 3.94 (dd, J ) 10.3, 5.3 Hz, 1H), 4.00 (d, J )
12.3 Hz, 1H), 5.02 (d, J ) 12.3 Hz, 1H), 5.48 (dd, J ) 10.4, 5.4
Hz, 1H), 5.56 (d, J ) 5.1 Hz, 1H), 9.81 (d, J ) 1.5 Hz, 1H); 13
C
NMR (C6D6, 50 MHz) δ 14.8 (q), 16.1 (q), 20.4 (q), 20.5 (q),
21.0 (t), 22.1 (t), 32.3 (t, 2C), 32.5 (t, 2C), 35.9 (d), 40.3 (s),
41.9 (d), 42.1 (d), 43.9 (s), 47.9 (d), 60.5 (t), 67.9 (t), 74.7 (d),
85.7 (d), 107.7 (d), 169.2 (s), 169.5 (s), 202.3 (d); MS m/z
(relative intensity) 113 (100); HRMS calcd for C24H35O7 (M+
- 1) 435.2383, found 435.2383 (σ ) 0.510 mmu); HRMS calcd
for C22H32O5 (M+ - 60) 376.2250, found 376.2245 (σ ) 0.134
mmu).
(1S,3R,4S,4a S,8S,8a S,2′S,3a ′R,6a ′S)-Acetic Acid 1-Ac-
etoxy-8-br om o-8-for m yldecah ydr o-4-(h exah ydr ofu r o[2,3-
b]fu r a n -2′-yl)-3,4-d im eth yln a p h th a len -8a -ylm eth yl Ester
(28). To a stirred solution of CH2Cl2 (5 mL) and 27 (35 mg,
8.3 × 10-5 mol) was added pyrrolidone‚HBr‚Br2 (82 mg, 16.5
× 10-5 mol). The reaction mixture was stirred for 5 d at room
temperature. After this period, CH2Cl2 (30 mL) was added,
followed by a saturated aqueous NaHCO3 solution (4 mL). The
aqueous phase was extracted with CH2Cl2 (10 mL). The
combined organic layers were washed with brine, dried, and
evaporated. The residue was purified by flash chromatography
was used directly in the next reaction: [R]20 -13.6 (c 1.8,
D
CHCl3); 1H NMR (CDCl3, 200 MHz) δ 0.90 (d, J ) 6.3 Hz, 3H),
0.99 (s, 3H), 1.12-2.21 (m, 14H), 1.33 (s, 3H), 1.45 (s, 3H),
2.78 (m, 1H), 3.37 (brd, J ) 5.1 Hz, 1H), 3.83 (m, 3H), 4.08
(dd, J ) 11.1, 5.7 Hz, 1H), 4.15 (d, J ) 12.4 Hz, 1H), 4.21 (dd,
J ) 12.5, 4.4 Hz, 1H), 5.57 (d, J ) 5.1 Hz, 1H), 9.92 (s, 1H);
13C NMR (CDCl3, 50 MHz) δ 15.4 (q), 17.2 (q), 21.2 (t), 21.6
(t), 23.4 (t), 26.4 (q), 29.3 (q), 32.3 (t), 32.7 (t), 34.9 (t), 35.2
(d), 40.3 (s), 41.3 (s), 42.0 (d), 42.2 (d), 50.2 (d), 60.2 (t), 68.3
(t), 73.9 (d), 86.5 (d), 98.5 (s), 108.0 (d), 205.7 (s); MS m/z
(relative intensity) 113 (100); HRMS calcd for C23H36O5 (M+)
392.2563, found 392.2552 (σ ) 0.262 mmu).
(35% EA/PE) to give 28 (26.8 mg, 5.2 × 10-5 mol) (63%): [R]20
D
1
33.1 (c 1.6, CHCl3); H NMR (C6D6, 200 MHz) δ 0.54 (d, J )
6.5 Hz, 3H), 0.84 (s, 3H), 1.05-1.89 (m, 11H), 1.59 (s, 3H),
1.79 (s, 3H), 2.00-2.52 (m, 4H), 3.58 (m, 2H), 3.88 (dd, J )
11.1, 5.2 Hz, 1H), 4.09 (d, J ) 12.3 Hz, 1H), 4.96 (d, J ) 12.3
Hz, 1H), 5.46 (dd, J ) 10.2, 3.5 Hz, 1H), 5.52 (d, J ) 5.1 Hz,
1H), 9.81 (s, 1H); 13C NMR (C6D6, 50 MHz) δ 14.2 (q), 16.0 (q),
20.0 (q), 20.8 (q), 21.8 (t), 22.0 (t), 30.5 (t), 32.2 (t), 32.4 (t),
32.6 (t), 35.93 (d), 40.3 (s), 41.9 (d), 43.5 (d), 50.2 (s), 60.6 (t),
67.9 (t), 77.5 (d), 85.3 (d), 87.5 (s), 107.6 (d), 168.4 (s), 168.9
(s), 188 (d); MS m/z (relative intensity) 113 (100); HRMS calcd
for C24H35O7 (M+ - Br) 435.2383, found 435.2382 (σ ) 0.325
mmu).
(2*,2a S,5a R,6S,7R,8a S,8bR,2′S,3a ′R,6a ′S)-Acetic Acid
2a -Br om o-8b-for m yld eca h yd r o-6-(h exa h yd r ofu r o[2,3-b]-
fu r a n -2′-yl)-6,7-d im eth yln a p h th o[1,8-bc]fu r a n -2-ylm eth -
yl Ester (29). To a stirred solution of 28 (16 mg, 3.1 × 10-5
mol) in MeOH (4 mL) was added MeONa (1.0 M in MeOH,
0.1 mL) at 0 °C. After 20 min, an aqueous solution of HCl (0.5
M, 10 mL) was added. The aqueous phase was extracted three
times with ethyl acetate. The combined organic layers were
washed with brine, dried, and evaporated. The residue was
purified by flash chromatography (60% EA/PE) to give 29 (11
mg, 2.3 × 10-5 mol) (75%): 1H NMR (C6D6, CD3OD, 200 MHz)
δ 0.58 (d, J ) 6.0 Hz, 3H), 0.66 (s, 3H), 0.82-2.52 (m, 16H),
1.90 (s), 3H), 3.54 (m, 2H), 3.90 (dd, J ) 11.4, 5.7 Hz, 1H),
4.03 (d, J ) 9.0 Hz, 1H), 4.14 (d, J ) 9.0 Hz, 1H), 5.20 (m,
1H), 5.48 (d, 5.1 Hz, 1H), 6.00 (s, 1H); 13C NMR (C6D6, 50 MHz)
δ 13.7 (q), 16.1 (q), 21.3 (q), 22.1 (t), 23.0 (t), 32.2 (t), 32.8 (t),
33.4 (t), 33.5 (t), 35.9 (d), 41.0 (s), 42.2 (d), 43.0 (d), 53.0 (s),
65.9 (t), 68.2 (t), 74.9 (s), 78.9 (d), 84.9 (d), 103.6 (d), 107.9 (d),
To a stirred solution of the aldehyde (18 mg, 4.7 × 10-5 mol)
in CH2Cl2 (4 mL) was added pyrrolidone‚HBr‚Br2 (36 mg, 7.0
× 10-5 mol). After 5 min, the reaction mixture was filtered
through a silica filter, the filter was washed thoroughly with
ethyl acetate. The solvents were evaporated to give 30 (12 mg,
3.4 × 10-5 mol, 73%) as a white powder: 1H NMR (C6D6, CD3-
OD, 200 MHz) δ 0.69 (d, J ) 6.9 Hz, 3H), 0.71 (s, 3H), 0.71-
2.05 (m, 17H), 2.27 (m, 1H), 3.37 (dd, J ) 11.3, 4.6 Hz, 1H),
3.60 (m, 2H), 3.88 (d, J ) 9.0 Hz, 1H), 3.99 (dd, J ) 11.4, 5.6
Hz, 1H), 4.19 (dd, J ) 11.4, 9.0 Hz, 1H), 5.08 (s, 1H), 5.54 (d,
5.1 Hz, 1H); 13C NMR (C6D6, CD3OD, 50 MHz) δ 13.4 (q), 16.7
(q), 22.5 (t), 23.3 (t), 28.4 (t), 32.4 (t), 32.8 (t), 36.2 (d), 37.3 (t),
41.2 (s), 42.1 (d), 43.8 (d), 50.7 (s), 54.5 (d), 68.1 (t), 68.5 (t),
77.6 (d), 85.2 (d), 104.6 (d), 108.0 (d); MS m/z (relative
intensity) 113 (100); HRMS calcd for C20H30O4 (M+ - 18)
334.2144, found 334.2148 (σ ) 0.126 mmu).
(2a S,5a R,6S,7R,8a S,8bR,2′S,3a ′R,6a ′S)-Acetic Acid 2a -
Deca h yd r o-6-(h exa h yd r ofu r o[2,3-b]fu r a n -2′-yl)-6,7-d i-
m eth yln a p h th o[1,8-bc]fu r a n -8b-ylm eth yl Ester (35). A
solution of 31 (30 mg, 7.7 × 10-5 mol) dissolved in MeOH (30
mL) was purged through with ozone at -78 °C until a pale
bleu color appeared. Then nitrogen was purged through,
followed by addition of NaBH4 (20 mg). The reaction mixture
was allowed to come to room temperature and stirred for an
additional 3 h. After this period water (10 mL) was added. The
aqueous phase was extracted three times with ethyl acetate.
The combined organic layers were washed with brine, dried,
and evaporated. The remaining alcohol 32 was dissolved in
pyridine (5 mL), followed by addition of MsCl (0.2 mL) at 0

Total Synthesis of Dihydroclerodin
J . Org. Chem., Vol. 64, No. 25, 1999 9187
°C. The reaction mixture was stirred for 3 h. Then ether (30
mL) was added, followed by water (15 mL). The aqueous phase
was extracted three times with ether. The combined organic
layers were washed with brine, dried, and evaporated. The
residue was purified by flash chromatography (60% EA/PE)
to give mesylate 33 (30 mg, 6.9 × 10-5 mol, 90%): 1H NMR
(CDCl3, 200 MHz) δ 0.85 (s, 3H), 0.87 (d, J ) 6.6 Hz, 3H),
1.16-2.16 (m, 14H), 2.69-2.95 (m, 4H), 3.02 (s, 3H), 3.65 (m,
1H), 3.84 (m, 3H), 4.03 (dd, J ) 11.1, 5.4 Hz, 1H), 4.23 (d, J )
11.7 Hz, 1H), 4.39 (dd, J ) 9.9, 7.0 Hz, 1H), 4.57 (dd, J ) 9.9,
5.6 Hz, 1H), 5.56 (d, J ) 5.1 Hz, 1H); 13C NMR (CDCl3, 50
MHz) δ 15.5 (q), 17.0 (q), 21.5 (t), 22.3 (t), 23.3 (t), 32.5 (t),
32.8 (t), 33.4 (d), 35.8 (d), 36.4 (t), 37.5 (q), 40.5 (s), 41.8 (d),
42.1 (d), 45.0 (s), 61.1 (t), 68.3 (t), 70.8 (d), 74.8 (d), 85.9 (d),
107.7 (d).
Hz, 1H), 4.91 (dd, J ) 11.0, 7.8 Hz, 1H), 5.10 (dd, J ) 11.0,
4.8 Hz, 1H), 5.64 (d, J ) 5.0 Hz, 1H); 13C NMR (C6D6, 50 MHz)
δ 15.8 (q), 18.38 (q), 18.45 (q), 21.5 (t), 22.6 (t), 23.9 (t), 26.3
(q), 27.4 (q), 27.4 (t), 32.6 (t), 32.6 (d), 32.8 (t), 34.8 (d), 37.7
(d), 40.0 (s), 40.7 (d), 41.9 (d), 41.9 (s), 60.7 (t), 67.9 (t), 73.3
(d), 74.3 (t), 85 3 (d), 98.8 (s), 108.1 (d); MS m/z (relative
intensity) 113 (100); HRMS calcd for C25H40O5S2 (M+) 484.2317,
found 484.2314 (σ ) 6.453 mmu, 4 scans); HRMS calcd for
C
23H36O4 (M+ - 108) 376.2614, found 376.2610 (σ ) 0.174
mmu).
(4a S ,6R ,7S ,7a R ,11a R ,2′S ,3a ′R ,6a ′S )-7-(H e xa h yd r o-
fu r o[2,3-b]fu r a n -2′-yl)-3,3,6,7-t e t r a m e t h yl-11-m e t h yl-
en eocta h yd r on a p h th o[1,8a -d ][1,3]d ioxin e (38). A solution
of degassed and freshly distilled dodecane (5 mL) and 37 (61
mg, 0.13 mmol) was heated for 48 h at reflux temperature (216
°C). Then the solvent was evaporated until 1 mL of the volume
remained, followed by flash chromatography (10% EA/PE) to
To a solution of 33 (30 mg, 6.9 × 10-5 mol) in DMF (5 mL)
and HMPA (1.0 mL) were added LiBr (30 mg) and Li2CO3 (26
mg). The reaction mixture was heated at 100 °C for 12 h. Then
the reaction mixture was cooled, followed by addition of water
(20 mL). The aqueous phase was extracted three times with
ethyl acetate. The combined organic layers were washed with
brine, dried, and evaporated. The residue was purified by flash
chromatography (60% EA/PE) to give 34 (15.8 mg, 4.7 × 10-5
mol, 61%): 1H NMR (CDCl3, 200 MHz) δ 0.83 (s, 3H), 1.03 (d,
J ) 6.7 Hz, 3H), 1.16-2.20 (m, 15H), 2.35 (m, 1H), 2.81 (m,
1H), 3.14-3.29 (m, 3H), 3.85 (m, 2H), 3.92 (dd, J ) 10.7, 5.4
Hz, 1H), 4.08 (d, J ) 10.8 Hz, 1H), 4.22 (dd, J ) 8.6, 8.6 Hz,
1H), 5.61 (d, J ) 5.1 Hz, 1H); 13C NMR (CDCl3, 50 MHz) δ
16.7 (q), 17.8 (t), 19.3 (q), 20.9 (t), 22.5 (t), 32.3 (t), 33.4 (t),
34.4 (t), 35.0 (d), 40.6 (d), 40.9 (d), 41.5 (s), 42.3 (d), 46.6 (s),
64.6 (t), 68.2 (t), 75.7 (t), 86.6 (d), 86.8 (d), 108.1 (d); MS m/z
(relative intensity) 113 (100).
give 38 (35 mg, 9.3 × 10-5 mol, 74%) as a colorless oil: [R]20
D
1
13.2 (c 0.43 CH2Cl2); H NMR (C6D6, 200 MHz) δ 0.80 (d, J )
6.8 Hz, 3H), 1.15 (s, 3H), 1.05-1.80 (m, 10H), 1.56 (s, 6H),
2.15-2.39 (m, 5H), 3.66 (m, 2H), 3.96 (d, J ) 12.1 Hz, 1H),
4.06 (dd, J ) 11.2, 5.4 Hz, 1H), 4.21 (dd, J ) 12.3, 5.0 Hz,
1H), 4.22 (d, J ) 12.1 Hz, 1H), 5.10 (bs, 1H), 5.44 (bs, 1H),
5.62 (d, J ) 5.0 Hz, 1H); 13C NMR (C6D6, 50 MHz) δ 15.0 (q),
17.2 (q), 22.6 (t), 27.9 (q), 28.8 (q), 28.8 (t), 32.6 (t), 33.0 (t),
34.0 (t), 36.2 (d), 36.6 (t), 41.3 (s), 42.3 (d), 45.6 (s), 49.4 (d),
61.1 (t), 68.2 (t), 74.3 (d), 86.0 (d), 99.0 (s), 108.2 (d), 108.4 (t),
153.7 (s); MS m/z (relative intensity) 361 (16), 113 (100); HRMS
calcd for C23H36O4 (M+) 376.2614, found 376.2609 (σ ) 0.308
mmu).
(1S,3R,4S,4aR,8aR,2′S,3a′R,6a′S)-Decah ydr o-4-(h exah y-
dr ofu r o[2,3-b]fu r an -2′-yl)-8a-h ydr oxym eth yl-3,4-dim eth yl-
8-m eth ylen en a p h th a len -1-ol (39). To a stirred solution of
38 (35 mg, 9.3 × 10-5 mol) in THF (20 mL) and water (10 mL)
was added one drop of (10%) trifluoroacetic acid. The reaction
mixture was stirred for 4 h. After this period, a saturated
aqueous NaHCO3 solution (5 mL) was added, followed by
evaporation of THF. The aqueous phase was extracted three
times with ethyl acetate. The combined organic layers were
washed with brine, dried, and evaporated. The residue was
purified by flash chromatography (60% EA/PE) to give 39 (23
For proper structure elucidation alcohol 34 was converted
into its acetate 35.
To a stirred solution of 34 (15 mg, 4.7 × 10-5 mol) in pyridine
(2 mL) and Ac2O (0.3 mL) was added one crystal of DMAP.
The reaction mixture was stirred for 1 h. Then ether (20 mL)
was added, followed by water (10 mL). The aqueous phase was
extracted three times with ether. The combined organic layers
were washed with brine, dried, and evaporated. The residue
was purified by flash chromatography (40% EA/PE) to give
35 (13 mg, 3.4 × 10-5 mol, 73%): [R]20 -16.5 (c 1.3, CHCl3);
mg, 7.0 × 10-5 mmol, 75%) as a colorless oil: [R]20 17.0 (c
D
D
1H NMR (C6D6, 400 MHz) δ 0.90 (d, J ) 6.8 Hz, 3H), 1.03 (s,
3H), 1.24 (m, 4H), 1.42 (m, 1H), 1.62-1.90 (m, 7H), 1.85 (s,
3H), 2.07 (s, 3H), 2.38 (m, 1H), 3.27(dd, J ) 12.8, 4.3 Hz, 1H),
3.31 (dd, J ) 8.9, 6.7 Hz, 1H), 3.69 (ddd, J ) 8.5, 8.5, 4.2 Hz,
1H), 3.77 (ddd, J ) 8.5, 8.5, 6.7 Hz, 1H), 3.98 (dd, J ) 11.1,
5.1 Hz, 1H), 4.31 (dd, J ) 8.5, 8.5 Hz, 1H), 4.40 (d, J ) 11.5
Hz, 1H), 4.45 (d, J ) 11.5 Hz, 1H), 5.71 (d, J ) 5.1 Hz, 1H);
13C NMR (C6D6, 100 MHz) δ 16.2 (q), 18.6 (t), 18.7 (q), 20.5
(q), 21.3 (t), 23.1 (t), 32.2 (t), 33.1 (t), 34.3 (t), 34.5 (d), 41.3
(d), 41.6 (s), 41.7 (d), 42.2 (d), 45.3 (s), 67.3 (t), 67.8 (t), 74.7
(t), 85.5 (d), 85.8 (d), 108.0 (d), 170.1 (s); MS m/z (relative
intensity) 113 (100); HRMS calcd for C22H33O5 (M+ - 1)
377.23287, found 377.2324 (σ ) 0.139 mmu).
0.50 CH2Cl2); 1H NMR (C6D6, 200 MHz) δ 0.73 (d, J ) 6.7 Hz,
3H), 0.89 (s, 3H), 1.03-1.88 (m, 11H), 2.09-2.42 (m, 6H), 3.62
(m, 2H), 3.95 (m, 3H), 4.08 (d, J ) 10.8 Hz, 1H), 5.13 (bs, 1H),
5.40 (bs, 1H), 5.59 (d, J ) 5.1 Hz, 1H); 13C NMR (C6D6, 100
MHz) δ 15.0 (q), 17.0 (q), 23.2 (t), 29.2 (t), 32.8 (t), 33.0 (t),
34.6 (t), 36.2 (d), 37.5 (t), 41.3 (s), 42.4 (d), 49.5 (d), 52.0 (s),
61.1 (t), 68.2 (t), 75.3 (d), 85.6 (d), 108.1 (d), 109.7 (t), 152.8
(s); MS m/z (relative intensity) 113 (100); HRMS calcd for
C
20H32O4 (M+) 336.2301, found 336.2290 (σ ) 0.259 mmu),
calcd for C20H30O3 (M+ - 18) 318.2195, found 318.2188 (σ )
0.337 mmu).
Dih yd r ocler od in (1) a n d 4-epi-Dih yd r ocler od in (41).
To a stirred solution of CH2Cl2 (0.5 mL) and 39 (7.4 mg, 2.2 ×
10-5 mol) was added a mixture of Na2HPO4 (15 mg) and
m-CPBA (10 mg) in CH2Cl2 (0.5 mL). The reaction mixture
was stirred for 4 h. After this period, ethyl acetate (10 mL)
and water (5 mL) were added. The aqueous phase was
extracted two times with ethyl acetate. The combined organic
layers were washed with brine, dried, and evaporated. The
residue was dissolved in pyridine (0.3 mL) and acidic anhy-
dride (0.2 mL), followed by addition of one crystal of DMAP.
The reaction mixture was stirred for 4 h, followed by addition
of water (5 mL). The aqueous phase was extracted three times
with ethyl acetate. The combined organic layers were washed
with brine, dried, and evaporated. The residue was purified
by flash chromatography (60% EA/PE) to elute first 41 (2.5
(4aS,6R,7S,11S,11aR,2′S,3a′R,6a′S)-Dith iocar bon ic Acid
S-Meth yl Ester O-[7-(Hexa h yd r ofu r o[2,3-b]fu r a n -2′-yl)-
3,3,6,7-tetr a m eth ylocta h yd r on a p h th o[1,8a -d ][1,3]d ioxin -
11-ylm eth yl] Ester (37). To a stirred solution of the crude
alcohol 32 (100 mg, 0.25 mmol) in THF (20 mL) was added
sodium hydride (100 mg, 60% in mineral oil) at 0 °C. The
reaction mixture was stirred for 2 h, followed by addition of
CS2 (1 mL), and the reaction mixture was stirred for an
additional 1.5 h. After this period, MeI (0.5 mL) was added
and the reaction mixture was allowed to come to room
temperature and stirred overnight. Then ether (20 mL) was
added, followed by ice-water (10 mL). The aqueous phase was
extracted three times with ether. The combined organic layers
were washed with brine, dried, and evaporated. The residue
was purified by flash chromatography (10% EA/PE) to give
mg, 5.7 × 10-6 mol, 26%) as a colorless oil: [R]20 14.9 (c 0.21,
D
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 0.85 (d, J ) 6.4 Hz, 3H),
0.98 (s, 3H), 1.15 (m, 1H), 1.38-2.25 (m, 13H), 1.96 (s, 3H),
2.05 (s, 3H), 2.55 (d, J ) 4.4 Hz, 1H), 2.71 (d, J ) 4.4 Hz, 1H),
2.90 (m, 1H), 3.89 (m, 2H), 4.12 (dd, J ) 11.3, 5.5 Hz, 1H),
4.31 (d, J ) 12.0 Hz, 1H), 4.60 (dd, J ) 10.4, 6.2 Hz, 1H), 4.89
(d, J ) 12.0 Hz, 1H), 5.65 (d, J ) 5.1 Hz, 1H); 13C NMR (C6D6,
37 (61 mg, 0.13 mmol, 51%) as a colorless oil: [R]20 9.7 (c
D
1.25 CH2Cl2); 1H NMR (C6D6, 200 MHz) δ 0.91 (d, J ) 7.0 Hz,
3H), 1.00 (s, 3H), 1.00-1.82 (m, 12H), 1.48 (s, 3H), 1.49 (s,
3H), 1.95-2.40 (m, 3H), 2.23 (s, 3H), 3.14 (m, 1H), 3.68 (m,
2H), 3.80 (d, J ) 12.1 Hz, 1H), 3.98 (m, 2H), 4.09 (d, J ) 12.1

9188 J . Org. Chem., Vol. 64, No. 25, 1999
Meulemans et al.
100 MHz) δ 14.4 (q), 16.7 (q), 21.6 (q), 22.0 (q), 22.2 (t), 23.5
(t), 26.1 (t), 32.0 (t), 32.5 (t), 32.7 (t), 33.1 (t), 35.8 (d), 40.6 (s),
42.5 (d), 46.0 (d), 55.6 (s), 61.4 (t), 62.2 (t), 69.0 (t), 72.3 (d),
86.0 (d), 108.1 (d), 170.4 (s), 171.1 (s); MS m/z (relative
intensity) 113 (100); HRMS calcd for C22H33O6 (M+ - 43)
393.2277, found 393.2267 (σ ) 0.164 mmu).
400 MHz) δ 0.67 (d, J ) 6.8 Hz, 3H), 1.01 (s, 3H), 1.05 (m,
1H), 1.15-1.89 (m, 11H), 1.83 (s, 3H), 1.88 (s, 3H), 2.18-2.35
(m, 4H), 3.68 (m, 2H), 4.00 (dd, J ) 11.2, 5.2 Hz, 1H), 4.23 (d,
J ) 12.0 Hz, 1H), 4.95 (d, J ) 10.0 Hz, 1H), 5.21 (d, J ) 12.0
Hz, 1H), 5.40 (dd, J ) 10.8, 4.4, 1H), 5.63 (d, J ) 5.2 Hz, 1H);
13C NMR (C6D6, 100 MHz) δ 14.7 (q), 16.5 (q), 21.1 (q), 21.1
(q), 23.1 (t), 29.2 (t), 32.5 (t), 32.9 (t), 33.2 (t), 34.7 (t), 36.1 (d),
41.3 (s), 42.3 (d), 49.4 (s), 50.4 (d), 61.2 (t), 68.3 (t), 75.8 (d),
85.4 (d), 106.7 (t), 108.0 (d), 152.6 (s), 169.9 (s), 170.0 (s); MS
m/z (relative intensity) 113 (100); HRMS calcd for C24H36O6
(M+) 420.2512, found 420.2510 (σ ) 0.167 mmu).
Compound 1 (2.4 mg, 5.5 × 10-6 mol, 25%) was eluted next
as a colorless oil: [R]20D -9.6 (c 0.22, CHCl3); 1H NMR (CDCl3,
400 MHz) δ 0.88 (d, J ) 6.5 Hz, 3H), 0.98 (s, 3H), 1.04 (m,
1H), 1.37-1.95 (m, 11H), 1.97 (s, 3H), 2.13 (s, 3H), 2.10-2.23
(m, 3H), 2.24 (d, J ) 4.0 Hz, 1H), 2.91 (m, 1H), 3.00 (dd, J )
3.9, 2.3 Hz, 1H), 3.89 (m, 1H), 4.12 (dd, J ) 11.3, 5.5 Hz, 1H),
4.37 (d, J ) 12.2 Hz, 1H), 4.70 (dd, J ) 11.4, 4.8 Hz, 1H), 4.93
(d, J ) 12.2 Hz, 1H), 5.66 (d, J ) 5.1 Hz, 1H); 13C NMR (C6D6,
100 MHz) δ 14.6 (q), 17.0 (q), 21.7 (q), 21.8 (q), 22.6 (t), 25.4
(t), 32.8 (t), 33.0 (t), 33.1 (t), 33.7 (t), 36.4 (d), 40.8 (s), 42.5 (d),
45.9 (s), 48.5 (d), 48.9 (t), 62.1 (t), 65.5 (s), 69.0 (t), 72.3 (d),
85.7 (d), 108.1 (d), 170.7 (s), 171.5 (s); MS m/z (relative
intensity) 113 (100); HRMS calcd for C22H33O6 (M+ - 43)
393.2277, found 393.2273 (σ ) 0.278 mmu).
Ack n ow led gm en t . This investigation was sup-
ported by The Netherlands Foundation for Chemical
Research (SON) with financial aid from The Nether-
lands Organization for Scientific Research (NWO). We
thank A. van Veldhuizen for recording 1H and 13C
spectra and H. J ongejan and C. J . Teunis for mass
spectra data and elemental analyses.
Lu p u cin -C (40). A solution of pyridine (0.3 mL), Ac2O (0.2
mL), 39 (9.0 mg, 2.7 × 10-5 mol), and a trace of DMAP was
stirred for 4 h. Then water (5 mL) was added. The aqueous
phase was extracted three times with ether. The combined
organic layers were washed with brine, dried, and evaporated.
The residue was purified by flash chromatography (40% EA/
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
1, 11-13, 21, 23, 29-31, 33, 40, 41, and 43. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
PE) to give 40 (10 mg, 2.4 × 10-5 mol, 90%); H NMR (C6D6,
J O991151R